Keeping it Together. Axonal Transport to the Synapse and the Effects of Molecular Chaperones in Health and Disease

  • Christopher Sinadinos
  • Amrit Mudher


Robust intracellular transport along the axon facilitates the delivery and replacement of somally synthesised macromolecules to and from the synapse, and is thus essential for the maintenance of neuronal function. In contact with an intricate cytoskeletal network, multi-subunit motor complexes drive axonal ­transport during journeys through an axonal compartment that is relatively devoid of machineries for de novo protein synthesis and turnover. Very little is known about how these complex transport machineries are assembled and maintained within the axon. In this review, possible roles for molecular chaperone proteins in the ­maintenance of processive, appropriately regulated axonal transport are ­considered. When such transport quality control is compromised, as in the case of ­neurodegenerative proteinopathies, such as Parkinson’s, Alzheimer’s and Huntington’s diseases, pathological axonal transport disruption amidst aberrant protein folding and ­aggregation can result, severing an essential life-line and jeopardising synaptic function. How the stress-induced protein folding and aggregation-blocking functions of molecular chaperones are overcome in a range of pathological circumstances is also considered.


Molecular Chaperone Axonal Transport Motor Complex Axonal Swelling Torsional Dystonia 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


  1. Albin, R.L., A. Reiner, K.D. Anderson, L.S. Dure, B. Handelin, R. Balfour, W.O. Whetsell Jr., J.B. Penney, and A.B. Young (1992). Preferential loss of striato-external pallidal projection neurons in presymptomatic Huntington’s disease. Ann. Neurol. 31:425–430.PubMedGoogle Scholar
  2. Auluck, P.K., H.Y. Chan, J.Q. Trojanowski, V.M. Lee, and N.M. Bonini (2002). Chaperone ­suppression of alpha-synuclein toxicity in a Drosophila model for Parkinson’s disease. Science 295:865–868.PubMedGoogle Scholar
  3. Ball, M.J. and G.H. Murdoch (1997). Neuropathological criteria for the diagnosis of Alzheimer’s disease: are we really ready yet? Neurobiol. Aging 18:S3–S12.PubMedGoogle Scholar
  4. Black, M.M., M.H. Chestnut, I.T. Pleasure, and J.H. Keen (1991). Stable clathrin: uncoating protein (hsc70) complexes in intact neurons and their axonal transport. J. Neurosci. 11:1163–1172.PubMedGoogle Scholar
  5. Block-Galarza, J., K.O. Chase, E. Sapp, K.T. Vaughn, R.B. Vallee, M. DiFiglia, and N. Aronin (1997). Fast transport and retrograde movement of huntingtin and HAP 1 in axons. Neuroreport 8:2247–2251.PubMedGoogle Scholar
  6. Braak, H. and E. Braak (1991). Neuropathological stageing of Alzheimer-related changes. Acta Neuropathol. (Berl) 82:239–259.Google Scholar
  7. Brown, A. (2003). Axonal transport of membranous and nonmembranous cargoes: a unified ­perspective. J. Cell Biol. 160:817–821.PubMedGoogle Scholar
  8. Brown, J.R., P. Stafford, and G.M. Langford (2004). Short-range axonal/dendritic transport by myosin-V: a model for vesicle delivery to the synapse. J. Neurobiol. 58:175–188.PubMedGoogle Scholar
  9. Burkhardt, J.K., C.J. Echeverri, T. Nilsson, and R.B. Vallee (1997). Overexpression of the dynamitin (p50) subunit of the dynactin complex disrupts dynein-dependent maintenance of membrane organelle distribution. J. Cell Biol. 139:469–484.PubMedGoogle Scholar
  10. Carrettiero, D.C., I. Hernandez, P. Neveu, T. Papaginnakopouler, and K.S. Kosik (2009).Google Scholar
  11. Caldwell, G.A., S. Cao, E.G. Sexton, C.C. Gelwix, J.P. Bevel, and K.A. Caldwell (2003). Suppression of polyglutamine-induced protein aggregation in Caenorhabditis elegans by torsin proteins. Hum. Mol. Genet. 12:307–319.PubMedGoogle Scholar
  12. Carra, S., M. Sivilotti, A.T. Chavez Zobel, H. Lambert, and J. Landry (2005). HspB8, a small heat shock protein mutated in human neuromuscular disorders, has in vivo chaperone activity in cultured cells. Hum. Mol. Genet. 14:1659–1669.PubMedGoogle Scholar
  13. Carrettiero, D.C., I. Hernandez, P. Neven, T. Papaginnakopoulos, and K.S. Kosik (2009). The cochaperone BAG2 sweeps paired helical filament- insoluble tau from the microtubule. J. Neurosci. 29:2151–2161.Google Scholar
  14. Cash, A.D., G. Aliev, S.L. Siedlak, A. Nunomura, H. Fujioka, X. Zhu, A.K. Raina, H.V. Vinters, M. Tabaton, A.B. Johnson, M. Paula-Barbosa, J. Avila, P.K. Jones, R.J. Castellani, M.A. Smith, and G. Perry (2003). Microtubule reduction in Alzheimer’s disease and aging is independent of tau filament formation. Am. J. Pathol. 162:1623–1627.PubMedGoogle Scholar
  15. Cattaneo, E., C. Zuccato, and M. Tartari (2005). Normal huntingtin function: an alternative approach to Huntington’s disease. Nat. Rev. Neurosci. 6:919–930.PubMedGoogle Scholar
  16. Chan, E.Y., R. Luthi-Carter, A. Strand, S.M. Solano, S.A. Hanson, M.M. DeJohn, C. Kooperberg, K.O. Chase, M. DiFiglia, A.B. Young, B.R. Leavitt, J.H. Cha, N. Aronin, M.R. Hayden, and J.M. Olson (2002). Increased huntingtin protein length reduces the number of polyglutamine-induced gene expression changes in mouse models of Huntington’s disease. Hum. Mol. Genet. 11:1939–1951.PubMedGoogle Scholar
  17. Chang, D.T., G.L. Rintoul, S. Pandipati, and I.J. Reynolds (2006). Mutant huntingtin aggregates impair mitochondrial movement and trafficking in cortical neurons. Neurobiol. Dis. 22:388–400.PubMedGoogle Scholar
  18. Chuang, J.Z., H. Zhou, M. Zhu, S.H. Li, X.J. Li, and C.H. Sung (2002). Characterization of a brain-enriched chaperone, MRJ, that inhibits Huntingtin aggregation and toxicity independently. J. Biol. Chem. 277:19831–19838.PubMedGoogle Scholar
  19. Chung, C.Y., J.B. Koprich, H. Siddiqi, and O. Isacson (2009). Dynamic changes in presynaptic and axonal transport proteins combined with striatal neuroinflammation precede dopaminergic neuronal loss in a rat model of AAV alpha-synucleinopathy. J. Neurosci. 29:3365–3373.PubMedGoogle Scholar
  20. Coy, D.L., W.O. Hancock, M. Wagenbach, and J. Howard (1999). Kinesin’s tail domain is an inhibitory regulator of the motor domain. Nat. Cell Biol. 1:288–292.PubMedGoogle Scholar
  21. Crosby, A.H. (2003). Disruption of cellular transport: a common cause of neurodegeneration? Lancet Neurol. 2:311–316.PubMedGoogle Scholar
  22. Cuchillo-Ibanez, I., A. Seereeram, H.L. Byers, K.Y. Leung, M.A. Ward, B.H. Anderton, and D.P. Hanger (2008). Phosphorylation of tau regulates its axonal transport by controlling its binding to kinesin. FASEB J. 22:3186–3195.PubMedGoogle Scholar
  23. Dabir, D.V., J.Q. Trojanowski, C. Richter-Landsberg, V.M. Lee, and M.S. Forman (2004). Expression of the small heat-shock protein alphaB-crystallin in tauopathies with glial pathology. Am. J. Pathol. 164:155–166.PubMedGoogle Scholar
  24. Day, R.M., J.S. Gupta, and T.H. MacRae (2003). A small heat shock/alpha-crystallin protein from encysted Artemia embryos suppresses tubulin denaturation. Cell Stress. Chaperones. 8:183–193.PubMedGoogle Scholar
  25. de, W.S. and S.T. Brady (1989). Axonal transport of a clathrin uncoating ATPase (HSC70): a role for HSC70 in the modulation of coated vesicle assembly in vivo. J. Neurosci. Res. 23:433–440.Google Scholar
  26. Der, P.M. and R.A. Quinlan (2004). Neuronal diseases: small heat shock proteins calm your nerves. Curr. Biol. 14:R625–R626.Google Scholar
  27. Dhaenens, C.M., B.E. Van, S. Schraen-Maschke, F. Pasquier, A. Delacourte, and B. Sablonniere (2004). Association study of three polymorphisms of kinesin light-chain 1 gene with Alzheimer’s disease. Neurosci. Lett. 368:290–292.PubMedGoogle Scholar
  28. Dickey, C.A., J. Dunmore, B. Lu, J.W. Wang, W.C. Lee, A. Kamal, F. Burrows, C. Eckman, M. Hutton, and L. Petrucelli (2006). HSP induction mediates selective clearance of tau phosphorylated at proline-directed Ser/Thr sites but not KXGS (MARK) sites. FASEB J. 20:753–755.PubMedGoogle Scholar
  29. DiFiglia, M., E. Sapp, K.O. Chase, S.W. Davies, G.P. Bates, J.P. Vonsattel, and N. Aronin (1997). Aggregation of huntingtin in neuronal intranuclear inclusions and dystrophic neurites in brain. Science 277:1990–1993.PubMedGoogle Scholar
  30. Dixit, R., J.L. Ross, Y.E. Goldman, and E.L. Holzbaur (2008). Differential regulation of dynein and kinesin motor proteins by tau. Science 319:1086–1089.PubMedGoogle Scholar
  31. Dou, F., W.J. Netzer, K. Tanemura, F. Li, F.U. Hartl, A. Takashima, G.K. Gouras, P. Greengard, and H. Xu (2003). Chaperones increase association of tau protein with microtubules. Proc. Natl. Acad. Sci. U. S. A. 100:721–726.PubMedGoogle Scholar
  32. Ebneth, A., R. Godemann, K. Stamer, S. Illenberger, B. Trinczek, and E. Mandelkow (1998). Overexpression of tau protein inhibits kinesin-dependent trafficking of vesicles, mitochondria, and endoplasmic reticulum: implications for Alzheimer’s disease. J. Cell Biol. 143:777–794.PubMedGoogle Scholar
  33. Fayazi, Z., S. Ghosh, S. Marion, X. Bao, M. Shero, and P. Kazemi-Esfarjani (2006). A Drosophila ortholog of the human MRJ modulates polyglutamine toxicity and aggregation. Neurobiol. Dis. 24:226–244.PubMedGoogle Scholar
  34. Firdaus, W.J., A. Wyttenbach, C. Diaz-Latoud, R.W. Currie, and A.P. Arrigo (2006). Analysis of oxidative events induced by expanded polyglutamine huntingtin exon 1 that are differentially restored by expression of heat shock proteins or treatment with an antioxidant. FEBS J. 273:3076–3093.PubMedGoogle Scholar
  35. Fulga, T.A., I. Elson-Schwab, V. Khurana, M.L. Steinhilb, T.L. Spires, B.T. Hyman, and M.B. Feany (2007). Abnormal bundling and accumulation of F-actin mediates tau-induced neuronal degeneration in vivo. Nat. Cell Biol. 9:139–148.PubMedGoogle Scholar
  36. Galigniana, M.D., C. Radanyi, J.M. Renoir, P.R. Housley, and W.B. Pratt (2001). Evidence that the peptidylprolyl isomerase domain of the hsp90-binding immunophilin FKBP52 is involved in both dynein interaction and glucocorticoid receptor movement to the nucleus. J. Biol. Chem. 276:14884–14889.PubMedGoogle Scholar
  37. Galvin, J.E., K. Uryu, V.M. Lee, and J.Q. Trojanowski (1999). Axon pathology in Parkinson’s disease and Lewy body dementia hippocampus contains alpha-, beta-, and gamma-synuclein. Proc. Natl. Acad. Sci. U. S. A. 96:13450–13455.PubMedGoogle Scholar
  38. Garcia, M.L. and D.W. Cleveland (2001). Going new places using an old MAP: tau, microtubules and human neurodegenerative disease. Curr. Opin. Cell Biol. 13:41–48.PubMedGoogle Scholar
  39. Garcia-Mata, R., Z. Bebok, E.J. Sorscher, and E.S. Sztul (1999). Characterization and dynamics of aggresome formation by a cytosolic GFP-chimera. J. Cell Biol. 146:1239–1254.PubMedGoogle Scholar
  40. Gauthier, L.R., B.C. Charrin, M. Borrell-Pages, J.P. Dompierre, H. Rangone, F.P. Cordelieres, M.J. De, M.E. MacDonald, V. Lessmann, S. Humbert, and F. Saudou (2004). Huntingtin controls neurotrophic support and survival of neurons by enhancing BDNF vesicular transport along microtubules. Cell 118:127–138.PubMedGoogle Scholar
  41. Gibbons, I.R. (1996). The role of dynein in microtubule-based motility. Cell Struct. Funct. 21:331–342.PubMedGoogle Scholar
  42. Gibson, P.H. (1987). Ultrastructural abnormalities in the cerebral neocortex and hippocampus associated with Alzheimer’s disease and aging. Acta Neuropathol. (Berl) 73:86–91.Google Scholar
  43. Granata, A., R. Watson, L.M. Collinson, G. Schiavo, and T.T. Warner (2008). The dystonia-associated protein torsinA modulates synaptic vesicle recycling. J. Biol. Chem. 283:7568–7579.PubMedGoogle Scholar
  44. Gunawardena, S. and L.S. Goldstein (2001). Disruption of axonal transport and neuronal viability by amyloid precursor protein mutations in Drosophila. Neuron 32:389–401.PubMedGoogle Scholar
  45. Gunawardena, S., L.S. Her, R.G. Brusch, R.A. Laymon, I.R. Niesman, B. Gordesky-Gold, L. Sintasath, N.M. Bonini, and L.S. Goldstein (2003). Disruption of axonal transport by loss of huntingtin or expression of pathogenic polyQ proteins in Drosophila. Neuron 40:25–40.PubMedGoogle Scholar
  46. Halliday, G., M.T. Herrero, K. Murphy, H. McCann, F. Ros-Bernal, C. Barcia, H. Mori, F.J. Blesa, and J.A. Obeso (2009). No Lewy pathology in monkeys with over 10 years of severe MPTP Parkinsonism. Mov Disord. 24:1519–1523.PubMedGoogle Scholar
  47. Hands, S., C. Sinadinos, and A. Wyttenbach (2008). Polyglutamine gene function and dysfunction in the ageing brain. Biochim. Biophys. Acta 1779:507–521.PubMedGoogle Scholar
  48. Hernandez, F. and J. Avila (2007). Tauopathies. Cell Mol. Life Sci. 64:2219–2233.PubMedGoogle Scholar
  49. Hewett, J.W., J. Zeng, B.P. Niland, D.C. Bragg, and X.O. Breakefield (2006). Dystonia-causing mutant torsinA inhibits cell adhesion and neurite extension through interference with cytoskeletal dynamics. Neurobiol. Dis. 22:98–111.PubMedGoogle Scholar
  50. Hirokawa, N. (1982). Cross-linker system between neurofilaments, microtubules, and membranous organelles in frog axons revealed by the quick-freeze, deep-etching method. J. Cell Biol. 94:129–142.PubMedGoogle Scholar
  51. Hirokawa, N. (1998). Kinesin and dynein superfamily proteins and the mechanism of organelle transport. Science 279:519–526.PubMedGoogle Scholar
  52. Hirokawa, N. and R. Takemura (2005). Molecular motors and mechanisms of directional transport in neurons. Nat. Rev. Neurosci. 6:201–214.PubMedGoogle Scholar
  53. Hoffner, G., S. Soues, and P. Djian (2007). Aggregation of expanded huntingtin in the brains of patients with Huntington disease. Prion 1:26–31.PubMedGoogle Scholar
  54. Horiuchi, D., C.A. Collins, P. Bhat, R.V. Barkus, A. Diantonio, and W.M. Saxton (2007). Control of a kinesin-cargo linkage mechanism by JNK pathway kinases. Curr. Biol. 17:1313–1317.PubMedGoogle Scholar
  55. Ishihara, T., M. Hong, B. Zhang, Y. Nakagawa, M.K. Lee, J.Q. Trojanowski, and V.M. Lee (1999). Age-dependent emergence and progression of a tauopathy in transgenic mice overexpressing the shortest human tau isoform. Neuron 24:751–762.PubMedGoogle Scholar
  56. Ittner, L.M., Y.D. Ke, and J. Gotz (2009). Phosphorylated tau interacts with c-JUN N-terminal kinase (JNK) interacting protein 1 (JIP1) in Alzheimer’s disease. J. Biol. Chem. 284:28909–28916.Google Scholar
  57. Jana, N.R., M. Tanaka, G. Wang, and N. Nukina (2000). Polyglutamine length-dependent interaction of Hsp40 and Hsp70 family chaperones with truncated N-terminal huntingtin: their role in suppression of aggregation and cellular toxicity. Hum. Mol. Genet. 9:2009–2018.PubMedGoogle Scholar
  58. Jenner, P. (2008). Functional models of Parkinson’s disease: a valuable tool in the development of novel therapies. Ann. Neurol. 64 Suppl 2:S16–S29.PubMedGoogle Scholar
  59. Jensen, P.H., M.S. Nielsen, R. Jakes, C.G. Dotti, and M. Goedert (1998). Binding of alpha-synuclein to brain vesicles is abolished by familial Parkinson’s disease mutation. J. Biol. Chem. 273:26292–26294.PubMedGoogle Scholar
  60. Johnston, J.A., C.L. Ward, and R.R. Kopito (1998). Aggresomes: a cellular response to misfolded proteins. J. Cell Biol. 143:1883–1898.PubMedGoogle Scholar
  61. Kamm, C., H. Boston, J. Hewett, J. Wilbur, D.P. Corey, P.I. Hanson, V. Ramesh, and X.O. Breakefield (2006). The early onset dystonia protein torsinA interacts with kinesin light chain 1. J.Biol.Chem. 279:19882–19892.Google Scholar
  62. Klopfenstein, D.R., M. Tomishige, N. Stuurman, and R.D. Vale (2002). Role of phosphatidylinositol(4,5)bisphosphate organization in membrane transport by the Unc104 kinesin motor. Cell 109:347–358.PubMedGoogle Scholar
  63. Klucken, J., Y. Shin, E. Masliah, B.T. Hyman, and P.J. McLean (2004). Hsp70 reduces alpha-synuclein aggregation and toxicity. J. Biol. Chem. 279:25497–25502.PubMedGoogle Scholar
  64. Koushika, S.P. (2008). “JIP”ing along the axon: the complex roles of JIPs in axonal transport. Bioessays 30:10–14.PubMedGoogle Scholar
  65. Koyama, Y. and J.E. Goldman (1999). Formation of GFAP cytoplasmic inclusions in astrocytes and their disaggregation by alphaB-crystallin. Am. J. Pathol. 154:1563–1572.PubMedGoogle Scholar
  66. Lee, D.W., J.B. Seo, B. Ganetzky, and Y.H. Koh (2009). DeltaFY mutation in human torsin A [corrected] induces locomotor disability and abberant synaptic structures in Drosophila. Mol. Cells 27:89–97.PubMedGoogle Scholar
  67. Lee, W.C., M. Yoshihara, and J.T. Littleton (2004). Cytoplasmic aggregates trap polyglutamine-containing proteins and block axonal transport in a Drosophila model of Huntington’s disease. Proc. Natl. Acad. Sci. U. S. A. 101:3224–3229.PubMedGoogle Scholar
  68. Leong, S.L., R. Cappai, K.J. Barnham, and C.L. Pham (2009). Modulation of alpha-synuclein aggregation by dopamine: a review. Neurochem. Res. 34:1838–1846.PubMedGoogle Scholar
  69. Lewis, J., E. McGowan, J. Rockwood, H. Melrose, P. Nacharaju, S.M. Van, K. Gwinn-Hardy, M.M. Paul, M. Baker, X. Yu, K. Duff, J. Hardy, A. Corral, W.L. Lin, S.H. Yen, D.W. Dickson, P. Davies, and M. Hutton (2000). Neurofibrillary tangles, amyotrophy and progressive motor disturbance in mice expressing mutant (P301L) tau protein. Nat. Genet. 25:402–405.PubMedGoogle Scholar
  70. Lewis, T.L. Jr., T. Mao, K. Svoboda, and D.B. Arnold (2009). Myosin-dependent targeting of transmembrane proteins to neuronal dendrites. Nat. Neurosci. 12:568–576.PubMedGoogle Scholar
  71. Li, W., P.N. Hoffman, W. Stirling, D.L. Price, and M.K. Lee (2004). Axonal transport of human alpha-synuclein slows with aging but is not affected by familial Parkinson’s disease-linked mutations. J. Neurochem. 88:401–410.PubMedGoogle Scholar
  72. Liang, P. and T.H. MacRae (1997). Molecular chaperones and the cytoskeleton. J. Cell Sci. 110 (Pt 13):1431–1440.PubMedGoogle Scholar
  73. Maloney, M.T., L.S. Minamide, A.W. Kinley, J.A. Boyle, and J.R. Bamburg (2005). Beta-secretase-cleaved amyloid precursor protein accumulates at actin inclusions induced in neurons by stress or amyloid beta: a feedforward mechanism for Alzheimer’s disease. J. Neurosci. 25:11313–11321.PubMedGoogle Scholar
  74. Marx, A., J. Muller, E.M. Mandelkow, A. Hoenger, and E. Mandelkow (2006). Interaction of kinesin motors, microtubules, and MAPs. J. Muscle Res. Cell Motil. 27:125–137.PubMedGoogle Scholar
  75. Mattson, M.P. (2004). Pathways towards and away from Alzheimer’s disease. Nature 430:631–639.PubMedGoogle Scholar
  76. McGuire, J.R., J. Rong, S.H. Li, and X.J. Li (2006). Interaction of Huntingtin-associated protein-1 with kinesin light chain: implications in intracellular trafficking in neurons. J. Biol. Chem. 281:3552–3559.PubMedGoogle Scholar
  77. McLean, P.J., H. Kawamata, S. Shariff, J. Hewett, N. Sharma, K. Ueda, X.O. Breakefield, and B.T. Hyman (2002). TorsinA and heat shock proteins act as molecular chaperones: suppression of alpha-synuclein aggregation. J. Neurochem. 83:846–854.PubMedGoogle Scholar
  78. Merienne, K., D. Helmlinger, G.R. Perkin, D. Devys, and Y. Trottier (2003). Polyglutamine expansion induces a protein-damaging stress connecting heat shock protein 70 to the JNK pathway. J. Biol. Chem. 278:16957–16967.PubMedGoogle Scholar
  79. Miller, R.L., M. James-Kracke, G.Y. Sun and A.Y. Sun (2009). Oxidative and inflammatory pathways in Parkinson’s disease. Neurochem. Res. 34:55–65.PubMedGoogle Scholar
  80. Mohan, P.M. and R.V. Hosur (2008). NMR characterization of structural and dynamics perturbations due to a single point mutation in Drosophila DLC8 dimer: functional implications. Biochemistry 47:6251–6259.PubMedGoogle Scholar
  81. Morfini, G., G. Pigino, N. Mizuno, M. Kikkawa, and S.T. Brady (2007a). Tau binding to microtubules does not directly affect microtubule-based vesicle motility. J. Neurosci. Res. 85:2620–2630.PubMedGoogle Scholar
  82. Morfini, G., G. Pigino, K. Opalach, Y. Serulle, J.E. Moreira, M. Sugimori, R.R. Llinas, and S.T. Brady (2007b). 1-Methyl-4-phenylpyridinium affects fast axonal transport by activation of caspase and protein kinase C. Proc. Natl. Acad. Sci. U. S. A. 104:2442–2447.PubMedGoogle Scholar
  83. Morfini, G., G. Szebenyi, R. Elluru, N. Ratner, and S.T. Brady (2002). Glycogen synthase kinase 3 phosphorylates kinesin light chains and negatively regulates kinesin-based motility. EMBO J. 21:281–293.PubMedGoogle Scholar
  84. Morfini, G.A., Y.M. You, S.L. Pollema, A. Kaminska, K. Liu, K. Yoshioka, B. Bjorkblom, E.T. Coffey, C. Bagnato, D. Han, C.F. Huang, G. Banker, G. Pigino, and S.T. Brady (2009). Pathogenic huntingtin inhibits fast axonal transport by activating JNK3 and phosphorylating kinesin. Nat. Neurosci. 12:864–871.PubMedGoogle Scholar
  85. Muchowski, P.J. and J.L. Wacker (2005). Modulation of neurodegeneration by molecular chaperones. Nat. Rev. Neurosci. 6:11–22.PubMedGoogle Scholar
  86. Mudher, A., D. Shepherd, T.A. Newman, P. Mildren, J.P. Jukes, A. Squire, A. Mears, J.A. Drummond, S. Berg, D. MacKay, A.A. Asuni, R. Bhat, and S. Lovestone (2004). GSK-3beta inhibition reverses axonal transport defects and behavioural phenotypes in Drosophila. Mol. Psychiatry 9:522–530.PubMedGoogle Scholar
  87. Muraro, N.I. and K.G. Moffat (2006). Down-regulation of torp4a, encoding the Drosophila ­homologue of torsinA, results in increased neuronal degeneration. J. Neurobiol. 66:1338–1353.PubMedGoogle Scholar
  88. Nakagawa, T., M. Setou, D. Seog, K. Ogasawara, N. Dohmae, K. Takio, and N. Hirokawa (2000). A novel motor, KIF13A, transports mannose-6-phosphate receptor to plasma membrane through direct interaction with AP-1 complex. Cell 103:569–581.PubMedGoogle Scholar
  89. Newmyer, S.L. and S.L. Schmid (2001). Dominant-interfering Hsc70 mutants disrupt multiple stages of the clathrin-coated vesicle cycle in vivo. J. Cell Biol. 152:607–620.PubMedGoogle Scholar
  90. Oddo, S., A. Caccamo, B. Tseng, D. Cheng, V. Vasilevko, D.H. Cribbs, and F.M. LaFerla (2008). Blocking Abeta42 accumulation delays the onset and progression of tau pathology via the C terminus of heat shock protein70-interacting protein: a mechanistic link between Abeta and tau pathology. J. Neurosci. 28:12163–12175.PubMedGoogle Scholar
  91. Ogura, T. and A.J. Wilkinson (2001). AAA+ superfamily ATPases: common structure–diverse function. Genes Cells 6:575–597.PubMedGoogle Scholar
  92. Oka, M., M. Nakai, T. Endo, C.R. Lim, Y. Kimata, and K. Kohno (1998). Loss of Hsp70-Hsp40 chaperone activity causes abnormal nuclear distribution and aberrant microtubule formation in M-phase of Saccharomyces cerevisiae. J. Biol. Chem. 273:29727–29737.PubMedGoogle Scholar
  93. Omran, H., D. Kobayashi, H. Olbrich, T. Tsukahara, N.T. Loges, H. Hagiwara, Q. Zhang, G. Leblond, E. O’Toole, C. Hara, H. Mizuno, H. Kawano, M. Fliegauf, T. Yagi, S. Koshida, A. Miyawaki, H. Zentgraf, H. Seithe, R. Reinhardt, Y. Watanabe, R. Kamiya, D.R. Mitchell, and H. Takeda (2008). Ktu/PF13 is required for cytoplasmic pre-assembly of axonemal dyneins. Nature 456:611–616.PubMedGoogle Scholar
  94. Ozelius, L.J., J.W. Hewett, C.E. Page, S.B. Bressman, P.L. Kramer, C. Shalish, L.D. de, M.F. Brin, D. Raymond, D.P. Corey, S. Fahn, N.J. Risch, A.J. Buckler, J.F. Gusella, and X.O. Breakefield (1997). The early-onset torsion dystonia gene (DYT1) encodes an ATP-binding protein. Nat. Genet. 17:40–48.PubMedGoogle Scholar
  95. Perng, M.D., L. Cairns, P. van de Ijssel, A. Prescott, A.M. Hutcheson, and R.A. Quinlan (1999). Intermediate filament interactions can be altered by HSP27 and alphaB-crystallin. J. Cell Sci. 112 (Pt 13):2099–2112.PubMedGoogle Scholar
  96. Petrucelli, L., D. Dickson, K. Kehoe, J. Taylor, H. Snyder, A. Grover, M. De Lucia, E. McGowan, J. Lewis, G. Prihar, J. Kim, W.H. Dillmann, S.E. Browne, A. Hall, R. Voellmy, Y. Tsuboi, T.M. Dawson, B. Wolozin, J. Hardy, and M. Hutton (2004). CHIP and Hsp70 regulate tau ubiquitination, degradation and aggregation. Hum. Mol. Genet. 13:703–714.PubMedGoogle Scholar
  97. Pilling, A.D., D. Horiuchi, C.M. Lively, and W.M. Saxton (2006). Kinesin-1 and Dynein are the primary motors for fast transport of mitochondria in Drosophila motor axons. Mol. Biol. Cell 17:2057–2068.PubMedGoogle Scholar
  98. Polymeropoulos, M.H., C. Lavedan, E. Leroy, S.E. Ide, A. Dehejia, A. Dutra, B. Pike, H. Root, J. Rubenstein, R. Boyer, E.S. Stenroos, S. Chandrasekharappa, A. Athanassiadou, T. Papapetropoulos, W.G. Johnson, A.M. Lazzarini, R.C. Duvoisin, I.G. Di, L.I. Golbe, and R.L. Nussbaum (1997). Mutation in the alpha-synuclein gene identified in families with Parkinson’s disease. Science 276:2045–2047.PubMedGoogle Scholar
  99. Pratt, W.B., A.M. Silverstein, and M.D. Galigniana (1999). A model for the cytoplasmic trafficking of signalling proteins involving the hsp90-binding immunophilins and p50cdc37. Cell Signal. 11:839–851.PubMedGoogle Scholar
  100. Qin, Z.H., Y. Wang, E. Sapp, B. Cuiffo, E. Wanker, M.R. Hayden, K.B. Kegel, N. Aronin, and M. DiFiglia (2004). Huntingtin bodies sequester vesicle-associated proteins by a polyproline-dependent interaction. J. Neurosci. 24:269–281.PubMedGoogle Scholar
  101. Reiner, A., R.L. Albin, K.D. Anderson, C.J. D’Amato, J.B. Penney, and A.B. Young (1988). Differential loss of striatal projection neurons in Huntington disease. Proc. Natl. Acad. Sci. U. S. A. 85:5733–5737.PubMedGoogle Scholar
  102. Renkawek, K., G.J. Bosman, and W.W. de Jong (1994). Expression of small heat-shock protein hsp 27 in reactive gliosis in Alzheimer disease and other types of dementia. Acta Neuropathol. (Berl) 87:511–519.Google Scholar
  103. Robinson, P.A. (2008). Protein stability and aggregation in Parkinson’s disease. Biochem. J. 413:1–13.PubMedGoogle Scholar
  104. Roher, A.E., N. Weiss, T.A. Kokjohn, Y.M. Kuo, W. Kalback, J. Anthony, D. Watson, D.C. Luehrs, L. Sue, D. Walker, M. Emmerling, W. Goux, and T. Beach (2002). Increased A beta peptides and reduced cholesterol and myelin proteins characterize white matter degeneration in Alzheimer’s disease. Biochemistry 41:11080–11090.PubMedGoogle Scholar
  105. Rose, S.E., F. Chen, J.B. Chalk, F.O. Zelaya, W.E. Strugnell, M. Benson, J. Semple, and D.M. Doddrell (2000). Loss of connectivity in Alzheimer’s disease: an evaluation of white matter tract integrity with colour coded MR diffusion tensor imaging. J. Neurol. Neurosurg. Psychiatry 69:528–530.PubMedGoogle Scholar
  106. Ross, C.A. and M.A. Poirier (2004). Protein aggregation and neurodegenerative disease. Nat. Med. 10 Suppl:S10–S17.PubMedGoogle Scholar
  107. Rui, Y., P. Tiwari, Z. Xie, and J.Q. Zheng (2006). Acute impairment of mitochondrial trafficking by beta-amyloid peptides in hippocampal neurons. J. Neurosci. 26:10480–10487.PubMedGoogle Scholar
  108. Saha, A.R., J. Hill, M.A. Utton, A.A. Asuni, S. Ackerley, A.J. Grierson, C.C. Miller, A.M. Davies, V.L. Buchman, B.H. Anderton, and D.P. Hanger (2004). Parkinson’s disease alpha-synuclein mutations exhibit defective axonal transport in cultured neurons. J. Cell Sci. 117:1017–1024.PubMedGoogle Scholar
  109. Sahara, N., M. Murayama, T. Mizoroki, M. Urushitani, Y. Imai, R. Takahashi, S. Murata, K. Tanaka, and A. Takashima (2005). In vivo evidence of CHIP up-regulation attenuating tau aggregation. J. Neurochem. 94:1254–1263.PubMedGoogle Scholar
  110. Sanchez, C., R. Padilla, R. Paciucci, J.C. Zabala, and J. Avila (1994). Binding of heat-shock protein 70 (hsp70) to tubulin. Arch. Biochem. Biophys. 310:428–432.PubMedGoogle Scholar
  111. Sapp, E., J. Penney, A. Young, N. Aronin, J.P. Vonsattel, and M. DiFiglia (1999). Axonal transport of N-terminal huntingtin suggests early pathology of corticostriatal projections in Huntington disease. J. Neuropathol. Exp. Neurol. 58:165–173.PubMedGoogle Scholar
  112. Shen, H.Y., J.C. He, Y. Wang, Q.Y. Huang, and J.F. Chen (2005). Geldanamycin induces heat shock protein 70 and protects against MPTP-induced dopaminergic neurotoxicity in mice. J. Biol. Chem. 280:39962–39969.PubMedGoogle Scholar
  113. Shimamoto, S., M. Takata, M. Tokuda, F. Oohira, H. Tokumitsu, and R. Kobayashi (2008). Interactions of S100A2 and S100A6 with the tetratricopeptide repeat proteins, Hsp90/Hsp70-organizing protein and kinesin light chain. J. Biol. Chem. 283:28246–28258.PubMedGoogle Scholar
  114. Shimoji, M., L. Zhang, A.S. Mandir, V.L. Dawson, and T.M. Dawson (2005). Absence of inclusion body formation in the MPTP mouse model of Parkinson’s disease. Brain Res. Mol. Brain Res. 134:103–108.PubMedGoogle Scholar
  115. Shimura, H., Y. Miura-Shimura, and K.S. Kosik (2004a). Binding of tau to heat shock protein 27 leads to decreased concentration of hyperphosphorylated tau and enhanced cell survival. J. Biol. Chem. 279:17957–17962.PubMedGoogle Scholar
  116. Shimura, H., D. Schwartz, S.P. Gygi, and K.S. Kosik (2004b). CHIP-Hsc70 complex ubiquitinates phosphorylated tau and enhances cell survival. J. Biol. Chem. 279:4869–4876.PubMedGoogle Scholar
  117. Sinadinos, C., T. Burbidge-King, D. Soh, L. Thompson, L. Marsh, A. Wyttenbach, and A.K. Mudher (2009). Live axonal transport disruption by mutant huntingtin fragments in Drosophila motor neuron axons. Neurobiol. Dis. 34:389–395.PubMedGoogle Scholar
  118. Sipione, S., D. Rigamonti, M. Valenza, C. Zuccato, L. Conti, J. Pritchard, C. Kooperberg, J.M. Olson, and E. Cattaneo (2002). Early transcriptional profiles in huntingtin-inducible striatal cells by microarray analyses. Hum. Mol. Genet. 11:1953–1965.PubMedGoogle Scholar
  119. Sousa, R. and E.M. Lafer (2006). Keep the traffic moving: mechanism of the Hsp70 motor. Traffic. 7:1596–1603.PubMedGoogle Scholar
  120. Spang, A. (2008). The life cycle of a transport vesicle. Cell Mol. Life Sci. 65:2781–2789.PubMedGoogle Scholar
  121. Spillantini, M.G., M.L. Schmidt, V.M. Lee, J.Q. Trojanowski, R. Jakes, and M. Goedert (1997). Alpha-synuclein in Lewy bodies. Nature 388:839–840.PubMedGoogle Scholar
  122. Stagi, M., P.S. Dittrich, N. Frank, A.I. Iliev, P. Schwille, and H. Neumann (2005). Breakdown of axonal synaptic vesicle precursor transport by microglial nitric oxide. J. Neurosci. 25:352–362.PubMedGoogle Scholar
  123. Stamer, K., R. Vogel, E. Thies, E. Mandelkow, and E.M. Mandelkow (2002). Tau blocks traffic of organelles, neurofilaments, and APP vesicles in neurons and enhances oxidative stress. J. Cell Biol. 156:1051–1063.PubMedGoogle Scholar
  124. Stokin, G.B., C. Lillo, T.L. Falzone, R.G. Brusch, E. Rockenstein, S.L. Mount, R. Raman, P. Davies, E. Masliah, D.S. Williams, and L.S. Goldstein (2005). Axonopathy and transport deficits early in the pathogenesis of Alzheimer’s disease. Science 307:1282–1288.PubMedGoogle Scholar
  125. Sun, Y. and T.H. MacRae (2005). Small heat shock proteins: molecular structure and chaperone function. Cell Mol. Life Sci. 62:2460–2476.PubMedGoogle Scholar
  126. Szebenyi, G., G.A. Morfini, A. Babcock, M. Gould, K. Selkoe, D.L. Stenoien, M. Young, P.W. Faber, M.E. MacDonald, M.J. McPhaul, and S.T. Brady (2003). Neuropathogenic forms of huntingtin and androgen receptor inhibit fast axonal transport. Neuron 40:41–52.PubMedGoogle Scholar
  127. Tai, A.W., J.Z. Chuang, C. Bode, U. Wolfrum, and C.H. Sung (1999). Rhodopsin’s carboxy-terminal cytoplasmic tail acts as a membrane receptor for cytoplasmic dynein by binding to the dynein light chain Tctex-1. Cell 97:877–887.PubMedGoogle Scholar
  128. Taylor, J.P., F. Tanaka, J. Robitschek, C.M. Sandoval, A. Taye, S. Markovic-Plese, and K.H. Fischbeck (2003). Aggresomes protect cells by enhancing the degradation of toxic polyglutamine-containing protein. Hum. Mol. Genet. 12:749–757.PubMedGoogle Scholar
  129. The Huntington’s Disease Collaborative Research Group (1993). A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington’s disease chromosomes. Cell 72:971–983.Google Scholar
  130. Tobaben, S., P. Thakur, R. Fernandez-Chacon, T.C. Sudhof, J. Rettig, and B. Stahl (2001). A trimeric protein complex functions as a synaptic chaperone machine. Neuron 31:987–999.PubMedGoogle Scholar
  131. Torroja, L., H. Chu, I. Kotovsky, and K. White (1999). Neuronal overexpression of APPL, the Drosophila homologue of the amyloid precursor protein (APP), disrupts axonal transport. Curr. Biol. 9:489–492.PubMedGoogle Scholar
  132. Trushina, E., R.B. Dyer, J.D. Badger, D. Ure, L. Eide, D.D. Tran, B.T. Vrieze, V. Legendre-Guillemin, P.S. McPherson, B.S. Mandavilli, H.B. Van, S. Zeitlin, M. McNiven, R. Aebersold, M. Hayden, J.E. Parisi, E. Seeberg, I. Dragatsis, K. Doyle, A. Bender, C. Chacko, and C.T. McMurray (2004). Mutant huntingtin impairs axonal trafficking in mammalian neurons in vivo and in vitro. Mol. Cell Biol. 24:8195–8209.PubMedGoogle Scholar
  133. Tsai M.Y., G. Morfini, G. Szebenyi, and S.T. Brady (2000). Release of kinesin from vesicles by hsc70 and regulation of fast axonal transport. Mol Biol Cell. 11:2161–2173.PubMedGoogle Scholar
  134. Tsvetkova, N.M., I. Horvath, Z. Torok, W.F. Wolkers, Z. Balogi, N. Shigapova, L.M. Crowe, F. Tablin, E. Vierling, J.H. Crowe, and L. Vigh (2002). Small heat-shock proteins regulate membrane lipid polymorphism. Proc. Natl. Acad. Sci. U. S. A. 99:13504–13509.PubMedGoogle Scholar
  135. Tukamoto, T., N. Nukina, K. Ide, and I. Kanazawa (1997). Huntington’s disease gene product, huntingtin, associates with microtubules in vitro. Brain Res. Mol. Brain Res. 51:8–14.PubMedGoogle Scholar
  136. Ungewickell, E., H. Ungewickell, S.E. Holstein, R. Lindner, K. Prasad, W. Barouch, B. Martin, L.E. Greene, and E. Eisenberg (1995). Role of auxilin in uncoating clathrin-coated vesicles. Nature 378:632–635.PubMedGoogle Scholar
  137. Vallee, R.B., J.C. Williams, D. Varma, and L.E. Barnhart (2004). Dynein: an ancient motor protein involved in multiple modes of transport. J. Neurobiol. 58:189–200.PubMedGoogle Scholar
  138. Verhey, K.J., D.L. Lizotte, T. Abramson, L. Barenboim, B.J. Schnapp, and T.A. Rapoport (1998). Light chain-dependent regulation of Kinesin’s interaction with microtubules. J. Cell Biol. 143:1053–1066.PubMedGoogle Scholar
  139. Viswanath, V., Y. Wu, R. Boonplueang, S. Chen, F.F. Stevenson, F. Yantiri, L. Yang, M.F. Beal, and J.K. Andersen (2001). Caspase-9 activation results in downstream caspase-8 activation and bid cleavage in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced Parkinson’s disease. J. Neurosci. 21:9519–9528.PubMedGoogle Scholar
  140. Walker, R.H., P.F. Good, and P. Shashidharan (2003). TorsinA immunoreactivity in inclusion bodies in trinucleotide repeat diseases. Mov Disord. 18:1041–1044.PubMedGoogle Scholar
  141. Webb, J.L., B. Ravikumar, and D.C. Rubinsztein (2004). Microtubule disruption inhibits autophagosome-lysosome fusion: implications for studying the roles of aggresomes in polyglutamine diseases. Int. J. Biochem. Cell Biol. 36:2541–2550.PubMedGoogle Scholar
  142. Wilhelmus, M.M., I. Otte-Holler, P. Wesseling, R.M. de Waal, W.C. Boelens, and M.M. Verbeek (2006). Specific association of small heat shock proteins with the pathological hallmarks of Alzheimer’s disease brains. Neuropathol. Appl. Neurobiol. 32:119–130.PubMedGoogle Scholar
  143. Williams, N.E. and E.M. Nelsen (1997). HSP70 and HSP90 homologs are associated with tubulin in hetero-oligomeric complexes, cilia and the cortex of Tetrahymena. J. Cell Sci. 110 (Pt 14):1665–1672.PubMedGoogle Scholar
  144. Wischik, C.M., M. Novak, H.C. Thogersen, P.C. Edwards, M.J. Runswick, R. Jakes, J.E. Walker, C. Milstein, M. Roth, and A. Klug (1988). Isolation of a fragment of tau derived from the core of the paired helical filament of Alzheimer disease. Proc. Natl. Acad. Sci. U. S. A. 85:4506–4510.PubMedGoogle Scholar
  145. Wyttenbach, A., J. Carmichael, J. Swartz, R.A. Furlong, Y. Narain, J. Rankin, and D.C. Rubinsztein (2000). Effects of heat shock, heat shock protein 40 (HDJ-2), and proteasome inhibition on protein aggregation in cellular models of Huntington’s disease. Proc. Natl. Acad. Sci. U. S. A. 97:2898–2903.PubMedGoogle Scholar
  146. Wyttenbach, A., O. Sauvageot, J. Carmichael, C. az-Latoud, A.P. Arrigo, and D.C. Rubinsztein (2002). Heat shock protein 27 prevents cellular polyglutamine toxicity and suppresses the increase of reactive oxygen species caused by huntingtin. Hum. Mol. Genet. 11:1137–1151.PubMedGoogle Scholar
  147. Wyttenbach, A., J. Swartz, H. Kita, T. Thykjaer, J. Carmichael, J. Bradley, R. Brown, M. Maxwell, A. Schapira, T.F. Orntoft, K. Kato, and D.C. Rubinsztein (2001). Polyglutamine expansions cause decreased CRE-mediated transcription and early gene expression changes prior to cell death in an inducible cell model of Huntington’s disease. Hum. Mol. Genet. 10:1829–1845.PubMedGoogle Scholar
  148. Yaglom, J.A., V.L. Gabai, A.B. Meriin, D.D. Mosser, and M.Y. Sherman (1999). The function of HSP72 in suppression of c-Jun N-terminal kinase activation can be dissociated from its role in prevention of protein damage. J. Biol. Chem. 274:20223–20228.PubMedGoogle Scholar
  149. Yamanaka, T., H. Miyazaki, F. Oyama, M. Kurosawa, C. Washizu, H. Doi, and N. Nukina (2008). Mutant Huntingtin reduces HSP70 expression through the sequestration of NF-Y transcription factor. EMBO J. 27:827–839.PubMedGoogle Scholar
  150. Zala, D., E. Colin, H. Rangone, G. Liot, S. Humbert, and F. Saudou (2008). Phosphorylation of mutant huntingtin at S421 restores anterograde and retrograde transport in neurons. Hum. Mol. Genet. 17:3837–3846.PubMedGoogle Scholar
  151. Zimmer, D.B., J. Chaplin, A. Baldwin, and M. Rast (2005). S100-mediated signal transduction in the nervous system and neurological diseases. Cell Mol. Biol. (Noisy-le-grand) 51:201–214.Google Scholar

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© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  1. 1.Southampton Neuroscience Group, School of Biological SciencesUniversity of SouthamptonSouthamptonUK

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